Project summary/abstract Dr. Al-bataineh?s career goals for the award period are to develop a research project and professional expertise that will enable him to develop scientific independence from his mentor and to establish his own career path to independent translational research in acute kidney injury. Dr. Al-bataineh will further his laboratory research and training by developing his proficiency in (i) validated animal models of renal injury including the two-kidney hanging-weight mouse model of ischemia-reperfusion injury (IRI), and mouse model of AKI-CKD progression, (ii) advanced approaches of kidney microscopy including multiphoton microscopy, three-dimensional imaging, and quantitative microscopic analyses, and (iii) technical expertise in molecular biology techniques such as ChIPseq and promoter-luciferase reporter assays. Dr. Al-bataineh plans to make the transition to an independent, tenure track position within 2-3 years of his mentored research training during this award. His long-term career goal is to become a fully independent academic investigator in the broad fields of renal physiology and kidney disease, performing research that provides insight into fundamental physiological problems that impact clinical issues, with a particular focus on AKI pathology, prevention, and treatment. ?-catenin signaling is a complex cellular response that is activated in renal tubules during kidney injury. While moderate ischemia results in transient induction of ?-catenin levels that associated with kidney protection, severe ischemia leads to sustained activation of the ?-catenin pathway and development of kidney fibrosis, implicating severity of injury as a key determinant of long term outcome. Emerging evidence supports a role for the transmembrane glycoprotein mucin 1 (MUC1 in humans, Muc1 in animals) in regulating ?-catenin activity. In tumor cells, (i) MUC1 directly binds to ?-catenin in the cytoplasm and nucleus, (ii) MUC1 blocks glycogen synthase kinase 3 ??(GSK3?)-mediated degradation of ?-catenin, and (iii) MUC1 overexpression correlates with increased levels of nuclear ?-catenin and its transcriptional activity. We previously reported that Muc1, found on the apical surface of normal kidney epithelia, plays a protective role in a mouse model of ischemia-reperfusion injury (IRI) by comparing kidney function and morphology in Muc1 KO mice and congenic control mice (AJP-Renal 2015; PMID: 25925251). Our recent studies showed that Muc1 induction and targeting to the nucleus after moderate ischemia was associated with increased ?-catenin levels and signaling (AJP-Renal 2016; PMID: 26739894). We also observed that sustained upregulation of Muc1 was also associated with prolonged induction of ?-catenin in mouse kidney homogenates at 7 d after severe ischemia. Based on these findings and on previous reports related to the acute and chronic effects of ?-catenin after kidney injury, we hypothesize that Muc1 protects against the early stages of AKI via transactivation of ?- catenin pathway, but persistent Muc1/?-catenin signaling after severe AKI leads to CKD progression and renal fibrosis. Our proposed studies will utilize both a mouse model of moderate and severe IRI, and a cultured human kidney cell line (HEK-293) after ATP depletion as an established model of ischemic cell injury. Moreover, we have already obtained mice with varying levels of Muc1 expression (Muc1 knockout, heterozygotes, and a transgenic overexpressing human MUC1) that will be used to assess if increased levels of Muc1 in the kidney in the short term enhance protection during IRI, while prolonged expression of Muc1 promotes kidney fibrosis. Successful completion of the proposed studies will provide important insight into the signaling pathways that are altered during IRI and repair, and will provide valuable information to help us design novel therapeutic strategies to treat AKI and prevent CKD progression.